Acute Respiratory Failure Associated

With Pulmonary Cryptococcosis in NonAIDS Patients*

Regis A. Vilchez, MD; Peter Linden, MD; Joan Lacomis, MD;
Philip Costello, MD; John Fung, MD; and Shimon Kusne, MD

Purpose: To determine the incidence of acute respiratory failure (ARF) in non-AIDS patients with
pulmonary cryptococcosis (PC).
Design: Retrospective cohort study.
Setting: University of Pittsburgh Medical Center, Pittsburgh, PA.
Subjects: All patients in whom PC without HIV infection was diagnosed between February 1989
and March 1999.
Results: Thirty-three patients with PC were identified, and 11 of those patients (33%) developed
ARF and comprised the study group. Underlying diseases included solid-organ transplant
recipients (seven patients; 64%) and other underlying medical conditions (four patients; 36%).
The most common symptoms were cough, shortness of breath, and temperature elevation.
Extrapulmonary involvement was seen in six patients (meningitis, four patients; peritonitis, one
patient; laryngeal mass, one patient). Six of the 11 patients (55%) died.
Conclusion: ARF may develop in one third of non-AIDS patients with PC. This clinical syndrome
is associated with the dissemination to extrapulmonary sites and high mortality rates. PC should
be recognized as a possible cause of respiratory failure in non-AIDS patients.
(CHEST 2001; 119:18651869)
Key words: acute respiratory failure; HIV status, negative; pulmonary cryptococcosis
Abbreviations: ARF acute respiratory failure; CSF cerebrospinal fluid; PC pulmonary cryptococcosis;
PEEP positive end-expiratory pressure

ryptococcus neoformans is a ubiquitous saproC phytic

fungus with a characteristic polysaccharide capsule. Its ecologic niche is poorly defined, but
it has been associated with pigeon and other bird
droppings. The point of entry for most cryptococcal
infections is thought to be the lung.1 The organism is
tropic for the CNS, and meningitis is the most
common presentation of the disease.2 Pulmonary
involvement in non-AIDS patients has been reported
in 10 to 29% of patients in whom cryptococcosis is
diagnosed.2,3 However, acute respiratory failure
(ARF) associated with pulmonary cryptococcosis

*From the Departments of Medicine (Drs. Vilchez and Kusne),

Surgery (Dr. Fung), Critical Care and Anesthesiology (Dr.
Linden), and Radiology (Drs. Costello and Lacomis), University
of Pittsburgh Medical Center, Pittsburgh, PA.
Manuscript received December 29, 1999; revision accepted
November 21, 2000.
Correspondence to: Shimon Kusne, MD, University of Pittsburgh
Medical Center, Division of Infectious Diseases, 501 Kaufmann
Bldg, 3471 Fifth Ave, Pittsburgh, PA 15213; e-mail:
kusnes2@msx.upmc.edu

(PC) has been given little emphasis in the literature

and has been alluded to only in the setting of HIV
infection.4,5
The aim of the present study was to determine the
incidence of ARF associated with PC in non-AIDS
patients and to identify the predictors of outcome
among these patients.

Materials and Methods

Identification of Cases
Patients with PC associated with ARF were selected from an
existing database of patients with cryptococcosis at The University of Pittsburgh Medical Center. Patients were identified by the
recovery of C neoformans from BAL fluid or lung histology/
pathology specimens. Patients were excluded from the study if
they had known HIV infection.
Definitions
Proven PC required abnormal findings on chest radiographs or
chest CT scans and isolation of C neoformans from BAL fluid
and/or lung histopathology specimen confirmation. Presumptive
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PC required abnormal findings on chest radiographs or chest CT

scan and isolation of C neoformans from at least one extrapulmonary site. ARF was defined as hypoxemia (ie, Po2 60 mm
Hg) requiring mechanical ventilation. Cryptococcus-related mortality was defined as death that was directly attributed to
cryptococcosis (ie, C neoformans had been recovered from
autopsy specimens). Patients who did not have an autopsy but
whose death occurred within 4 weeks of receiving a diagnosis of
PC also were considered to have Cryptococcus-related mortality.
Chart Review
The medical records of the study population were obtained and
reviewed for data collection from the electronic information
database of the hospital (Medical Archival Retrieval System).
Included in this database were the admission history and physical
examination results, the discharge summary, the dictated
progress notes, the record of medications that had been dispensed from the pharmacy, and all laboratory data, including
microbiology and pathology reports.
Demographic data including race, birth date, sex, dates of
admission and discharge, dates of organ transplant operations,
diagnostic procedures, and the outcome of the present hospitalization were obtained. The admission history and the physical
examination results were reviewed for the presence and duration
of fever, cough, and dyspnea, and patients were assessed for the
presence of respiratory failure and their requirement of mechanical ventilation.
Recorded microbiology data included the date, specimen site,
and results of cultures of all specimens, and the results of testing
of the Cryptococcus antigen in serum and cerebrospinal fluid
(CSF). Pathology data obtained included the date, specimen
type, and results of Grocott-Gomori methanamine-silver stains.
The cause of death was obtained from the discharge summary or
the autopsy report.
Chest Radiology
Chest radiographs and CT scans were reviewed by two thoracic
radiologists for the locations and types of pulmonary infiltrates
and for the presence of nodules, masses, pleural effusions, and
lymph node enlargement.
Statistical Analysis
Continuous variables were presented as the mean and SD, and
categoric variables were presented as proportions. The standard

two-sample t test was used to test differences between means,

while differences in proportions were tested using Fishers Exact
Test.

Results
Between February 1989 and March 1999, 33
patients with PC who did not have AIDS were
identified for study enrollment. The group included
22 recipients of solid-organ transplants and 11 nontransplant patients. Eleven patients (33%) developed
ARF, and they comprised the study group. The
incidence of ARF was equivalent between the transplant group (7 of 22 patients) and the nontransplant
group (4 of 11 patients). Of the 11 patients with
ARF, 7 had proven cases of PC and 4 had presumptive cases. Eight patients were men and three were
women. The mean age was 48 years (age range, 29 to
68 years). All 11 cases occurred in white individuals.
Of the seven solid-organ transplant recipients,
three had undergone heart transplants and four had
undergone liver transplants. All seven patients received long-term immunosuppressive therapy, which
included tacrolimus or cyclosporine with or without
prednisone. The time intervals between transplantation and the onset of PC were from 1 month to 10
years. Among the nontransplant patients, two had
chronic liver disease, one had congenital heart disease (dextrocardia), and one had lung cancer. Only
one patient in the nontransplant group had received
immunosuppressive therapy before the diagnosis
of PC, which consisted of chemotherapy for lung
cancer. Table 1 presents the clinical presentation,
microbiology, radiology findings, treatment, and outcome data of each study case. Common symptoms
were reported in 10 patients. The duration of symptoms ranged between 1 day and 30 days before
diagnosis. Sites of extrapulmonary involvement

Table 1Clinical Features, Treatment, and Outcome of Patients With ARF Associated With PC*
Patient
No.
1
2
3
4
5
6
7
8
9
10
11

Symptoms
SOB 14 d
SOB, cough
SOB 1 d
SOB, T 38.7C
SOB 10 d
SOB, T 38.3C
Cough 5 d, T 39C
T 41C
NR
Headache
SOB, cough 14 d,
T 38.6C

Mechanical
Ventilation, d

Culture Positive

Serum Cryptococcal
Antigen

Radiology

12
7
3
8
30
7
11
3
4
4
7

Blood, peritoneal fluid

BAL
BAL
BAL, CSF
Laryngeal mass
BAL
BAL, blood, CSF
BAL, CSF
BAL
CSF
BAL

1:1,024
NO
NO
1:128
1:68
Negative
1:1,024
NO
NO
1:32,768
NO

Bilateral effusion
Bilateral airspace disease
LUL airspace disease
Bilateral airspace disease
Bibasilar airspace disease
Right effusion
RUL airspace disease
Bilateral effusion
Bilateral airspace disease
Right effusion
RUL airspace disease

Treatment
AMPHO
None
AMPHO
AMPHO
AMPHO
AMPHO
AMPHO
AMPHO
None
AMPHO
None

Outcome

B/5FC Died
Died
B
Survived
B/5FC Died
B/5FC Survived
B/5FC Survived
B/5FC Survived
B
Survived
Died
B/5FC Died
Died

*SOB shortness of breath; T temperature; LUL left upper lobe; RUL right upper lobe; AMPHO B amphotericin B;
5FC flucytosine; NO not obtained; NR not reported.
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Clinical Investigations in Critical Care

were seen in six patients (55%), and they included

meningitis (n 4), peritonitis (n 1), and laryngeal
mass (n 1).
Mechanical ventilation was initiated in all 11 patients within 24 h of hospital admission. The duration
of ventilation support ranged from 3 to 30 days.
Therapy with positive end-expiratory pressure
(PEEP) was used in all patients and ranged between
7.5 and 10 cm H2O. Chest radiograph findings
included the following: irregular or nodular airspace
disease (nine patients), segmental or lobar airspace
disease (two patients), and pleural effusions (six
patients). Chest CT scans were performed in six
patients and provided additional information that
was not readily seen on plain chest radiographs that
had been performed in all patients. Chest radiographs of two of our patients in this study are shown
in Figures 1, 2.

Figure 2. Disseminated cryptococcosis and respiratory failure in

a liver transplant recipient. A portable chest radiograph (top) and
a CT scan (bottom) with patchy bilateral irregular and nodular
airspace opacities and small pleural effusions are shown.

Figure 1. Disseminated cryptococcosis and respiratory failure in

a liver transplant recipient. The initial portable chest radiograph
(top) shows bilateral airspace disease, which is worse peripherally
on the left. A follow-up chest radiograph (bottom) obtained 48 h
later shows a rapid progression of disease, now diffuse in the left
lung and extensive in the right lung.

The mean values for laboratory tests at the time

of diagnosis included the following: hematocrit,
30.5% (range, 24.9 to 37.3%); WBC count,
10,181/L (range 3,900 to 15,800 L); serum glucose level, 159.6 mg/dL (range, 93 to 322 mg/dL);
serum creatinine level, 2.1 mg/dL (range, 1.0 to 5.1
mg/dL); and arterial Po2 at a fraction of inspired
oxygen of 0.21, 53 mm Hg (range, 38 to 60 mm Hg).
Six of the 11 patients (55%) died. All deaths
occurred within 2 weeks of diagnosis. Three of the
six patients who died received their diagnoses after
death and did not receive treatment. The other three
patients had received treatment with amphotericin B
and flucytosine. An autopsy was performed in three
of the patients. Microscopic findings in these patients demonstrated disseminated cryptococcosis, involving multiple lung lobes (n 2), hilar and subcarinal lymph nodes (n 3), esophagus (n 1),
kidney (n 1), and CNS (n 1).
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Discussion
Although not conclusively documented, almost all
cases of cryptococcosis are thought to be the result of
the inhalation of fungi from an environmental
source. Indeed, desiccated yeast cells of C neoformans measuring 0.6 to 3.5 mm in diameter, a size
that is ideal for alveolar deposition after inhalation,
have been isolated from aerosol particles generated
from soil and pigeon droppings.6,7 After entry, the
fungus may remain dormant in the lung or spread to
another organ system with affinity to the CNS.
Before the AIDS era, the reported incidence of
pulmonary disease was 10%, but most of the cases were
identified histologically, and often at autopsy, with only
approximately 20% diagnosed by culture.2 A recent
study by Hajjeh et al3 showed a 29% incidence of PC in
HIV-negative patients. Cancer, a known risk factor for
cryptococcosis, was the most common underlying disease, followed by diabetes mellitus. However, most
patients in the study suffering from diabetes also had
one or more immunocompromising conditions. Perhaps the most likely explanation for this is the increased
use of immunosuppressive agents for a variety of
medical conditions.
Different authors have described the broad spectrum of PC in both HIV-infected and non-HIV
patients.2,8,9 However, reports of ARF in association
with cryptococcal infection have been described only
in the HIV-positive population. In a study4 of 210
patients with AIDS and cryptococcosis, ARF was
identified in 19 patients (14%). Nine of the patients
were definitively defined as having cases of PC, and
10 patients were defined as having probable cases.
Definitive cases were defined as patients with ARF
and bronchoscopic and/or autopsy evidence of pulmonary involvement with C neoformans, in the
absence of any other pulmonary process. Cases were
probable if, in the absence of bronchoscopic evidence, the patients with ARF had microbiological
evidence of extraneural dissemination of cryptococcosis with no other concurrent diagnosis. Mechanical
ventilation was used in only 7 of the 19 patients with
ARF. However, no data regarding the time between
the initiation of mechanical ventilation and the time
of diagnosis or the use of PEEP were given. All 19
patients with ARF had evidence of extrapulmonary
disease, including 10 patients who had meningitis.
The predictors of ARF included black race, a lactate
dehydrogenase level of 500 IU/L, and the presence of interstitial infiltrates and cutaneous lesions.
All patients died. Another report5 described a case of
ARDS and cryptococcosis in a 45-year-old white man
in whom AIDS had been diagnosed. Treatment with
mechanical ventilation with PEEP was started, but
the patient died 48 h after his admission to the
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hospital. A postmortem histopathologic examination

of the lungs showed diffuse bilateral PC.
Our cohort included non-AIDS patients who developed ARF in association with PC. All patients
required the initiation of mechanical ventilation
along with the addition of PEEP within 24 h after
their hospital admission. This rapid clinical presentation is suggestive of an acute lung injury, which is
in contrast with the subclinical pneumonitis that is
more often described in most reports concerning
non-AIDS patients.1,2,8 Possible explanations for this
observation may be related to the virulence factors of
C neoformans and its capacity to induce different
lung injuries as well as the hosts immune status.
Previous reports have shown that the prevalence of
cryptococcosis is markedly increased among patients
with defects in the cell-mediated arm of the immune
system, such as those in patients with AIDS, lymphoreticular malignancy, collagen vascular disease,
and sarcoidosis and in patients receiving immunosuppressive therapy.2,6,8 In our group, 7 of the 11
patients with ARF were solid-organ transplant recipients and were receiving immunosuppressive agents
to prevent acute allograft rejection, thus placing
them at risk for cryptococcal disease. Of the remaining four patients, three also had conditions that may
have altered their host status, such as lung cancer
and chronic liver disease. Therefore, they were also
at risk for cryptococcosis. The incidence of ARF in
both groups was equivalent.
Although we recognize that the etiology of ARF
associated with cryptococcal disease is a multifactorial one, the extent of cryptococcosis in the lungs and
other organs that is described in our study may have
played an important role in the pathogenesis of
respiratory failure. Our findings also confirm that
nonspecific symptoms are the predominant manifestation of PC.2,8 Thus, a high index of suspicion for
PC should remain in the differential diagnosis of
ARF in patients at risk.
Risk factors for poor outcome despite treatment
for cryptococcosis in non-AIDS patients were associated with meningitis. These factors include the
following: lymphoreticular malignancy; glucocorticoid therapy; CSF with high opening pressure; low
glucose level; 20 leukocytes/L; a positive reaction to an India ink smear; cryptococci isolated from
an extraneural site; and high titers of cryptococcal
antigen in the CSF or serum.10 In our study, the
presence of ARF in patients with cryptococcal disease yielded a mortality rate of 55% and often was
associated with disseminated disease. Thus, the presence of ARF with cryptococcosis is a particularly
grave prognostic sign, and it could represent a
marker of systemic cryptococcal infection.
In summary, ARF may develop in one third of
Clinical Investigations in Critical Care

non-AIDS patients with PC. Its incidence is equivalent among transplant recipients and patients with
other medical conditions, and it is associated with a
high mortality rate.

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